The present invention relates to processes for the production of key intermediates in the synthetic pathway leading to naturally occurring cytokinins, particularly trans-zeatin and dihydrozeatin.
Cytokinins are naturally occurring 6-substituted aminopurines, which are plant hormones known for their biological activity on plant growth. The more important of these effects are the abilities to induce cell division and regulate differentiation in excised plant tissue. Zeatin is one of the most active forms of the cytokinins.
Owing to the difficulty in isolating even minute quantities of the naturally occurring cytokinins, researchers have turned their efforts to investigating synthetic pathways to form biologically active 6-substituted aminopurines. For trans-zeatin, much of the research has been focused on a suitable synthesis of trans-3-hydroxymethylbut-2-enylamine (VI), the highly functionalized unsaturated side chain which can be condensed, by known methods, with 6-chloropurine to form trans-zeatin. In the case of dihydrozeatin (II), the desired side chain is 3-hydroxymethylbutylamine (VII).
Thus far, known methods for the synthesis of trans-3-hydroxymethylbut-2-enylamine fall into one of the following three categories:
1. A multistep synthesis involving an allylic bromination and starting with tiglic acid, see for example G. Shaw et al., J. Chem. Soc. (c), 921, 1966, and D. S. Letham et al., Phytochemistry, 10, 2077, 1971; PA1 2. A multistep synthesis starting from acetone and cyanoacetic acid and involving allylic bromination, see for example D. S. Letham et al., Aust. J. Chem., 22, 205, 1969; and PA1 3. A Gabriel phthalimide synthesis for the selective allylic amination, starting from isoprene or an isoprenoid halide, see for example M. Ohsugi et al., Agr. Biol. Chem., 38, 1925, 1974, R. Mornet et al., Tetrahedron Lett., 167, 1977, J. Corse et al., Synthesis, 618, 1972, and G. Desvages et al., Bull. Soc. Chim. Fr., 3329, 1969.
Generally the methods of the first two categories involve many steps, provide low yields and require the difficult separation of geometric isomers of the .alpha.,.beta.-unsaturated nitrile necessarily produced by an allylic bromination. The third method involves an unstable dibromide intermediate and requires an undesirable recrystallization step in order to separate an intermediate mixture.
By the method described by D. S. Letham et al., Aust. J. Chem., 22, 205, 1969, it is possible to selectively reduce trans-3-hydroxymethylbut-2-enenitrile (VIII) to trans-3-hydroxymethylbut-2-enylamine (VI) using 2-tetrahydropyranyl as a protecting group for the hydroxyl function. It must be pointed out that, on the basis of the present inventors experiences, lithium aluminum hydride reduction of the 2-tetrahydropyranyl ether of hydroxynitrile (VIII), after the procedure of Letham et al., invariably leads to a complex mixture of products, in which saturated amines are found to be main constituents. Otherwise the hydroxynitrile (VIII) can be exhaustively reduced to form 3-hydroxymethylbutylamine (VII). Condensation of the unsaturated or saturated amine with 6-chloropurine, by for example the method of Letham et al., is known to yield the trans-zeatin or dihydrozeatin.
It is therefore an object of the present invention to provide processes for the preparation of the unsaturated amino alcohol (VI) and the saturated amino alcohol (VII), which can then be transformed by known methods to trans-zeatin and dihydrozeatin respectively.
In a process described in U.S. Pat. No. 3,960,923 issued to DeSimone, .alpha.,.beta.-unsaturated nitriles can be prepared by reaction of a ketone and acetonitrile in the presence of a base. However, as reported in a publication by S. A. DiBiase et al., (Synthesis, 629, 1977) and as supported by the poor yield data presented by DeSimone, this base catalyzed condensation fails or gives very poor yields with methyl ketones.
Since the starting material for the synthesis of the desired unsaturated amino alochol (VI) or saturated amino alcohol (VII), using the reaction scheme of DeSimone, is necessarily a methyl ketone, this process is not feasible for an unactivated methyl ketone.